While nitric oxide (NO) is an essential intrinsic substance engaged in various homeostatic mechanisms, it can also serve as a causal substance of inflammation and the like. NO synthase (NOS) is an enzyme that catalyzes synthesis of NO using L-arginine as substrate and has three isoforms of iNOS, eNOS and nNOS.
iNOS, or inducible NO synthase, does not usually exhibit its enzymatic activity unlike other isoforms. However, upon stimulation of a cell by cytokine, LPS or the like, production of iNOS is induced and large amount of NO are transiently produced. This NO serves as a mediator of inflammation to cause, for example, septic shock, vasodilation due to the inflammation, hypotension, etc.
Similarly, cyclooxygenase 2 (COX-2) is known as an enzyme that is induced by stimulation of cytokines, growth factors etc. This enzyme also functions as a mediator of inflammatory response through production of prostaglandin.
Since these two inducible enzymes participate in major responsive pathways of inflammation, a discovery of a compound to inhibit iNOS and/or COX-2 has been considered to lead to creation of a novel anti-inflammatory agent (Mini Rev Med Chem vol. 8, p. 73-90, 2008).
On the other hand, the expression of iNOS and COX-2 has been known to be induced by activation of the transcription factor NF-κB, particularly in macrophages etc., and thus a development of an anti-inflammatory agent that inhibits expression of iNOS or COX-2 by inhibiting NF-κB has been anticipated.
Further, iNOS is expressed at high level in various tumors such as colon cancer and breast cancer. Since a DTCM glutarimide can inhibit tumoral transformation and metastases of tumor, it is useful as an anti-tumor agent. Proliferation of tumor cells can be suppressed when COX-2 in the tumor cells is inhibited. Because of this fact and other evidence, inhibitors of iNOS and COX-2 are expected also as anti-tumor agents.
However, an agent which inhibits expression of iNOS and COX-2 by inhibiting NF-κB also raises the risk of side effects due to the inhibition of NF-κB.